α1 type IV collagen (Col4) is a major component of the vascular basement membrane that lies beneath the endothelium and surrounds medial smooth muscle cells, and the overproduction of Col4 plays a crucial role in the process of diabetic angiopathy, arteriosclerosis and aging-related diseases. Prolonged exposure to hyperglycemia is now recognized as a significant causal factor of diabetic complications (non-patent documents 1 and 2). Excessive advanced glycation end-products (AGEs) produced as a result of hyperglycemia are known to induce a variety of cellular events in vascular cells and other cells, possibly through several functional AGEs receptors, thereby modulating the disease processes (non-patent documents 3, 4 and 5). AGEs have been recently accepted as playing an important role, not only in diabetic complications, but also in arteriosclerosis caused by aging (non-patent documents 6 and 7). Moreover, a truncated, soluble form of the receptor for AGEs was reported to inhibit the progress of accelerated diabetic atherosclerosis (non-patent document 8).
Morphologically, the progress of diabetic nephropathy is characterized by progressive thickening of the glomerular basement membrane (GBM) and by expansion of the mesangial extracellular matrix (ECM). Since Col4 is a major component of the thickened GBM and expanded ECM, it is important to clarify how Col4 is regulated at the transcriptional level in the diabetic state. The 130-bp bidirectional promoter of Col4 contains a large stem-loop structure (CIV) which has been shown to interact with several DNA binding proteins (non-patent documents 9). Using a gel mobility shift assay, the present inventors previously reported that an unknown protein binds to the CIV site only when Col4 is induced by the exposure to AGEs (non-patent document 10).
Both mesangial cell proliferation and glomerulosclerosis are major pathological features in progressive glomerular disorders. The fact that mesangial cell proliferation is observed in many glomerular sclerosing diseases suggests that this process is important in progressive glomerular disorders (non-patent document 11 (A1), non-patent document 12 (A2)). Both events are concomitantly observed in most of glomerular diseases, but it is not clear how cell proliferation is involved in the progress of glomerulosclerosis.
Platelet derived growth factor (PDGF) was shown as a critical mitogen for mesangial cells in vitro and in vivo (non-patent document 13 (3A), non-patent document 14 (4A)). Not only in experimental models but also in human glomerular diseases, it has been proved that PDGF plays a key role in the progress of glomerulosclerosis (non-patent document 13 (A3)). PDGF-BB was also reported to be essential for mesangial cell proliferation (non-patent document 15 (A5)), which is followed by development of glomerulosclerosis in a remnant kidney model (non-patent document 16 (A6)). Introduction of neutralizing anti-PDGF antibody markedly ameliorated both mesangial proliferation and glomerulosclerosis in a rat glomerulonephritis model (non-patent document 17 (A7)), but little was known about the mechanism how inhibition of cell proliferation reduces glomerular sclerotic lesions.    Non-patent document 1:    The Diabetes Control and Complications Trial Research Group. N. Engl. J. Med. 329, 977-986 (1993).    Non-patent document 2:    UK Prospective Diabetes Study (UKPDS) Group. Lancet 352, 837-853 (1998)    Non-patent document 3:    H. Vlassara, et al., Proc. Natl. Acad. Sci. USA 91, 11704-11708 (1994).    Non-patent document 4: M. Brownlee, A. Cerami, H. Vlassara, N. Engl. J. Med. 318, 1315-1321 (1988).    Non-patent document 5:    T. Doi, et al., Proc. Natl. Acad. Sci. USA 89, 2873-2877 (1992).    Non-patent document 6:    H. Vlassara, et al., Proc. Natl. Acad. Sci. USA 89, 12043-12047 (1992).    Non-patent document 7:    M. S. Huijberts, et al., J. Clin. Invest. 92, 1407-1411 (1993).    Non-patent document 8:    S. L. Park, et al., Nature Med. 9, 1025-1031 (1998)    Non-patent document 9:    L. A. Bruggeman, P. D. Burbelo, Y Yamada, P. E. Klotman, Oncogene 7, 1497-1502 (1992).    Non-patent document 10:    N. Iehara, H. Takeoka, Y. Yamada, T. Kita, T. Doi, Kidney Int. 50, 1166-1172 (1996).    Non-patent document 11:    Fogo A, Ichikawa I. Evidence for the central role of glomerular growth promoters in the development of sclerosis. Semin Nephrol. 1989 December; 9(4):329-42.    Non-patent document 12:    Striker L J, Doi T, Elliot S, Striker G E. The contribution of glomerular mesangial cells to progressive glomerulosclerosis. Semin Nephrol. 1989 December; 9(4):318-28. Review.    Non-patent document 13:    Floege J, Johnson R J: Multiple roles for platelet-derived growth factor in renal disease. Miner Electrolyte Metab 21: 271-282, 1995    Non-patent document 14:    Doi T, Vlassara H, Kirstein M, Yamada Y. Striker G E, Striker L J: Receptor-specific increase in extracellular matrix production by mesangial cells by advanced glycosylation end products is mediated via platelet-derived growth factor. Proc Natl Acad Sci USA 89: 2873-2877, 1992    Non-patent document 15:    Barnes J L, Hevey K A. Glomerular mesangial cell migration in response to platelet-derived growth factor. Lab Invest. 1990 Mar; 62(3):379-82.    Non-patent document 16:    Floege, J., Bums, M. W., Alpers, C. E., Yoshimura, A., Pritzl, P., Gordon, K., Seifert, R. A., Bowen-Pope, D. F., Couser, W. G., and Johnson, R. J.: Glomerular cell proliferation and PDGF expression precede glomerulosclerosis in the remnant kidney model. Kidney Int. 41: 297-309, 1992    Non-patent document 17:    Johnson, R. J., Raines, E. W., Floege, J, et al: Inhibition of mesangial cell proliferation and matrix expansion in glomerulonephritis in the rat by antibody to platelet-derived growth factor. J Exp Med 175: 1413-1416, 1992